Protective effect of peroxisome proliferator activator receptor (PPAR)-α and -γ ligands against methotrexate-induced nephrotoxicity

Context: The anticancer drug methotrexate (MTX) may cause multi-organ toxicities, including nephrotoxicity.

Objective: To investigate effects of peroxisome proliferator activator receptor (PPAR)-α and -γ agonists; fenofibrate (FEN) and pioglitazone (PIO), in MTX-induced nephrotoxicity in rats.

Methods: Rats were given FEN or PIO (150 or 5?mg/kg/day, respectively) orally for 15 days. MTX was injected as a single dose of 20?mg/kg, i.p. at day 11 of experiment, with or without either PPAR agonists.

Results: MTX induced renal toxicity, assessed by increase in serum urea and creatinine as well as histopathological alterations. MTX caused renal oxidative/nitrosative stress, indicated by decrease in GSH and catalase with increase in malondialdehyde and nitric oxide (NOx) levels. In addition, MTX increased renal level of the pro-inflammatory cytokine; tumor necrosis factor (TNF)-α and up-regulated the expression of both the inflammatory and apoptotic markers; NF-κB and caspase 3. Pre-administration of FEN or PIO to MTX-treated rats improved renal function and reversed oxidative/nitrosative parameters. Interestingly, pre-administration of PIO, but not FEN, decreased renal TNF-α level and NF-κB expression compared to MTX alone. Furthermore, PIO had more significant effect than FEN on reversing MTX-induced renal caspase 3 expression.

Discussion: Both FEN and PIO conferred protection against MTX-induced nephrotoxicity through comparable amelioration of oxidative/nitrosative stress. FEN lacked any effect on TNF-α/NF-κB, which was reflected on its less improvement on renal histopathology and apoptosis.

Conclusion: At indicated dosage, PPAR-γ ligand; PIO shows better improvement of MTX-induced nephrotoxicity compared to PPAR-α ligand; FEN due to differential effect on TNF-α/NF-κB inflammatory pathway.     

Surgery for metastatic neuroendocrine tumors with occult primaries

Introduction

Neuroendocrine tumors (NETs) frequently metastasize prior to diagnosis. Although metastases are often identifiable on conventional imaging studies, primary tumors, particularly those in the midgut, are frequently difficult to localize preoperatively.

Materials and methods

Patients with metastatic NETs with intact primaries were identified. Clinical and pathologic data were extracted from medical records. Primary tumors were classified as localized or occult based on preoperative imaging. The sensitivities and specificities of preoperative imaging modalities for identifying the primary tumors were calculated. Patient characteristics, tumor features, and survival in localized and occult cases were compared.

Results

Sixty-one patients with an intact primary tumor and metastatic disease were identified. In 28 of these patients (46%), the primary tumor could not be localized preoperatively. A median of three different preoperative imaging studies were utilized. Patients with occult primaries were more likely to have a delay (>6 mo) in surgical referral from time of onset of symptoms (57% versus 27%, P = 0.02). Among the 28 patients with occult primary tumors, 18 (64%) were found to have radiographic evidence of mesenteric lymphadenopathy corresponding, in all but one case, to a small bowel primary. In all but three patients (89%), the primary tumor could be identified intraoperatively.

Conclusion

The primary tumor can be identified intraoperatively in a majority of patients with metastatic NETs, irrespective of preoperative localization status. Referral for surgical management should not, therefore, be influenced by the inability to localize the primary tumor.     

Association between plasma levels of transforming growth factor-β1, IL-23 and IL-17 and the severity of autism in Egyptian children

It has been recently shown that dysregulation of transforming growth factor-β1 (TGF-β1), IL-23 and IL-17 has been identified as a major factor involved in autoimmune disorders. Based on the increasing evidence of immune dysfunction in autism the aim of this study was to measure serum levels of TGF-β 1, IL-23 and IL-17 in relation to the degree of the severity of autism. Serum TGF-β1, IL-23 and IL-17 were measured by Enzyme-linked Immunosorbent Assay technique in 50 autistic children aged 6–12 years, in comparison to 50 developmental disabilities and 50 typically developing-matched children. The severity of autism was assessed by using the Childhood Autism Rating Scale. We found that TGF-β1 and IL-23 levels were significantly decreased in the plasma of children with ASD in comparison to control groups (P < 0.0001 for both) with no significant difference in IL-17 levels. There was no correlation between IL-23 and TGF-β1 with IL-17 in children with ASD. There was a negative correlation between TGF-β1, IL-23 and IL-17 with the severity of autism (P < 0.0001, 0.0001, 0.005 respectively). Our results support the findings that immune dysfunction may occur in some children with autism.     

Early and Late Term Management in Caustic Ingestion in Children: A 16-year Experience

Accidental corrosive ingestion is one of the common problems causing serious esophageal strictures in children. The acute phase treatment has a great effect on stricture development. In this study we aim to present our experience in the management of caustic ingestion, particularly during the acute phase. From January 1990 to January 2005, 296 children were admitted to our clinic with caustic ingestion. Ninety-one patients who received dilatation treatment due to esophageal strictures constituted the present study group. Forty-three of them were admitted to our centre immediately after caustic ingestion (Group A) whereas 48 of them received some kind of treatment in other hospitals and were referred us with the diagnosis of stricture 6 to 12 weeks after ingestion (Group B). In the acute phase, the patients were given nothing orally until esophagoscopy was performed in the first 24–48 hours. The patients with grades 2b and 3 lesions underwent a week of esophageal rest by using a nasogastric tube. IV fluids and broad-spectrum antibiotics with a single-dose steroid were given. IV ranitidine was also added to the medical treatment. If there were stricture formations on barium meal after 3 weeks, these patients underwent esophageal dilatation programmes. The response rates to dilatation treatment were higher in group A. In addition, increased perforation rates were observed in group B. Sixty per cent of patients in group A but none of the patients in group B have recovered in the first year. In conclusion, after caustic ingestion, esophageal rest combined with supporting treatment seems to provide a good success rate with respect to prevention of stricture development and other troublesome complications.     

Simultaneous and Differential Fronto-orbital and Midface Distraction Osteogenesis for Syndromic Craniosynostosis Using Rigid External Distractor II

ABSTRACT: In syndromic craniosynostosis, the relation between the supraorbital area and the frontal bone is not good, and it is not possible to reform this area with 1-block advancement. To avoid this problem, the frontal bone is separated from the fronto-orbital bandeau, each is reshaped and remodeled separately, and then both are reattached.The retrusion of the midface, especially in syndromic craniosynostosis, is usually greater than that of cranial bones, so the technique usually separating the midface from the cranium is Le Fort III osteotomy, which allows differential distraction of each part.In this procedure, the cranial and midfacial bones are advanced simultaneously and differentially, both to the planned extent, in a single-stage operation, using rigid external distractor II, correcting exorbitism, respiratory embarrassment, and cranial structures and avoiding eye complications in the future. This procedure was used, with a follow-up, in 10 patients with syndromic craniosynostosis from 2 to 5 years.     

Meta-analysis of effect of dipeptidyl peptidase-4 inhibitors on cardiovascular risk in type 2 diabetes mellitus

Patients with type 2 diabetes mellitus (DM) have a very high risk for major adverse cardiovascular (CV) events. Previous studies have shown that traditional oral diabetic medications, despite lowering blood glucose levels, generally do not improve CV outcomes. The safety of some oral hypoglycemic medications has been questioned. We aimed to evaluate the CV safety of dipeptidyl peptidase-4 (DPP4) inhibitors, a novel class of oral diabetic medications, by performing a meta-analysis of DPP4 inhibitors for type 2 DM. A search of electronic databases of published and unpublished literature (until September 30, 2011) was performed to identify randomized controlled trials of ≥24 weeks that compared DPP4 inhibitors to other oral diabetic medications. A meta-analysis was performed using fixed and random effects to determine risk ratio (RR) for adverse CV events with DPP4 inhibitor monotherapy compared to other oral diabetic medications or to placebo. Eighteen randomized met our inclusion criteria, comprising 4,998 patients who were randomized to DPP4 inhibitors and 3,546 to a comparator, with a median duration of therapy of 46.4 weeks. In pooled analysis, the RR of any adverse CV event with a DPP4 inhibitor was 0.48 (0.31 to 0.75, p = 0.001), and the RR for nonfatal myocardial infarction or acute coronary syndrome was 0.40 (0.18 to 0.88, p = 0.02). In conclusion, this meta-analysis provides evidence that DPP4 inhibitors are safe from a CV standpoint and may possibly decrease risk of adverse CV events.     

Fibrocartilaginous embolism: a comprehensive review of an under-studied cause of spinal cord infarction and proposed diagnostic criteria

Background: Most spinal cord infarctions are due to aortic pathologies and aortic surgeries. Fibrocartilaginous Embolism (FCE) has been reported to represent 5.5% of spinal cord infarctions. Some believe that FCE is more common than presumed and is rather under-diagnosed due to vagueness surrounding its clinical presentation.

Method: A literature search was conducted for case reports of FCE published before August 2014. PubMed, the Cochrane Central Register and Google Scholar were searched for different combinations of the key words "fibrocartilaginous, "nucleus pulposus", "embolism", "spinal cord", "inter-vertebral disc", "infarction", "stroke", "paraplegia", "quadriplegia", "myelopathy".

Result: Fifty-five case articles were reviewed, ten of which were translated from foreign languages. A total of 67 cases of FCE were found, 41 tissue-confirmed and 26 clinically suspected. A comprehensive summary of the clinical anatomy, patho-physiologic mechanisms, epidemiology, diagnosis and treatment of FCE is described, along with the conflicting opinions on its incidence and relevance after reviewing all of the related literature. The 41 tissue proven cases are summarized and a schematic approach to the clinical diagnosis of FCE, deducted from their clinical findings, is presented.

Conclusion: FCE of the spinal cord, often mis-diagnosed as transverse myelitis, may be more common than presumed. Future research into FCE, including the development of a chondrolytic therapy that can be given empirically upon its clinical suspicion to acutely reverse its symptoms, may be of value.     

Infection after vertebroplasty or kyphoplasty. A series of nine cases and review of literature

Background contextPercutaneous augmentation with bone cement is a widely accepted modality of treatment for thoracic and lumbar vertebral osteoporotic fractures. Infection after vertebroplasty or kyphoplasty is a serious, yet, rarely reported complication.PurposeTo present a case series with a long-term follow-up of spinal infection after vertebroplasty/kyphoplasty with analysis of preoperative condition, risk factors, diagnostic findings, time before reoperation, causative organism, treatment, and outcome.Study designA retrospective, uncontrolled clinical case series in a single institution.Patient sampleBetween January 1997 and June 2012, 1,307 patients underwent percutaneous vertebroplasty or kyphoplasty. Six cases had postoperative infection (0.46%) and three additional cases were referred from other institutions for salvage treatment.Outcome measuresPerioperative assessment included visual analog scale, clinical, laboratory, and imaging findings, and activities of daily living at the end of the follow-up.MethodsNine patients were included: six females and three males (mean age 73.8 years). Comorbidities were found in all patients. Kyphoplasty had been done in five patients and vertebroplasty in four.ResultsThe interval between augmentation and revision surgery ranged from 10 to 395 days with a mean of 118.4 days. Three cases with early infection presented within 1 month. Infection parameters were high in all patients at readmission. All patients were treated surgically except one case who died before the planned revision surgery. In all cases, debridement and corpectomy were done through anterior approaches combined with posterior instrumentation. The most common causative organism was Staphylococcus aureus in three cases. Mean follow-up period after the revision surgery was 26.68 months, excluding two patients who died early in the follow-up (within 4 months). This amounts to a mortality rate of 33.3% perioperatively. At the end of follow-up, two patients had unrestricted activities and one patient required a walker. Of three paraparetic patients, two improved functionally and could walk unassisted and one improved but still used a wheelchair.ConclusionsAlthough vertebroplasty and kyphoplasty are minimally invasive interventions, postoperative infection can develop into life-threatening complications. This should be accounted for, in decision making in the elderly age group most commonly affected by osteoporotic fractures and especially in suspicious and high-risk immune-compromised patients.     

Case report: portal hypertension secondary to isolated liver tuberculosis

In this report, we present a case of isolated liver tuberculosis (TB) as a cause of non-cirrhotic portal hypertension leading to bleeding esophageal varices. Although TB has been known to cause portal hypertension in a variety of ways, this case was notable for the presence of periportal inflammation and granulomas, also seen in hepatic schistosomiasis. Herein, we discuss isolated liver TB and the differential diagnosis of non-cirrhotic portal hypertension. In endemic areas, TB should be considered in the differential diagnosis of non-cirrhotic portal hypertension.     

Ablation of vimentin results in defective steroidogenesis

In steroidogenic tissues, cholesterol must be transported to the inner mitochondrial membrane to be converted to pregnenolone as the first step of steroidogenesis. Whereas steroidogenic acute regulatory protein has been shown to be responsible for the transport of cholesterol from the outer to the inner mitochondrial membrane, the process of how cholesterol moves to mitochondria from the cytoplasm is not clearly defined. The involvement of the cytoskeleton has been suggested; however, no specific mechanism has been confirmed. In this paper, using genetic ablation of an intermediate filament protein in mice, we present data demonstrating a marked defect in adrenal and ovarian steroidogenesis in the absence of vimentin. Cosyntropin-stimulated corticosterone production is decreased 35 and 50% in male and female Vimentin null (Vim(-/-)) mice, respectively, whereas progesterone production is decreased 70% in female Vim(-/-) mice after pregnant mare's serum gonadotropin and human chorionic gonadotropin stimulation, but no abnormalities in human chorionic gonadotropin-stimulated testosterone production is observed in male Vim(-/-) mice. These defects in steroid production are also seen in isolated adrenal and granulosa cells in vitro. Further studies show a defect in the movement of cholesterol from the cytosol to mitochondria in Vim(-/-) cells. Because the mobilization of cholesterol from lipid droplets and its transport to mitochondria is a preferred pathway for the initiation of steroid production in the adrenal and ovary but not the testis and vimentin is a droplet-associated protein, our results suggest that vimentin is involved in the movement of cholesterol from its storage in lipid droplets to mitochondria for steroidogenesis.